DESCRIPTION (Verbatim from the Applicant): Bone cancer pain decreases the quality of life of millions of patients each year in the United States. Because there has not been an experimental model appropriate for studying osteolytic bone cancer pain, very little is known about its etiology, and current treatments can be ineffective or have unwanted side effects. We have very recently developed an experimental model for studying bone cancer pain. Features of this model are that it allows simultaneous quantitative evaluation of tumor growth, bone destruction, bone cell biology, painful behaviors, cellular biology of pain and neurochemistry of pain. Based on our unique capability to study bone cancer pain, we now propose to determine the cause of bone cancer pain in two types of bone cancers: those that stimulate bone destruction (osteolytic), and those that stimulate bone formation (osteoblastic). The long-range goal of our laboratories is to understand the pathophysiology of bone cancer and its sequelae and to use this knowledge to develop new treatments. The objective of this application is to determine the cause of bone cancer's most devastating sequalae: pain. To accomplish this, we will develop an experimental model for studying osteoblastic bone cancer pain and then use that model and our established osteolytic bone cancer model to determine the cause of bone cancer pain. The central hypothesis of this proposal is that bone cancer pain is caused by both the cancer itself and by cancer-induced bone loss. To test this hypothesis, the following Aims will be pursued: (1) establish the role of osteoclasts in the development of osteoblastic cancers; (2) define the characteristics of osteoblastic bone cancer pain; (3) determine if osteoblastic and/or osteolytic bone cancer tumors cause pain; and (4) determine if cancer-induced bone loss (osteoblastic and/or osteolytic) causes pain. At the completion of these Aims we expect to define the bone cell biology and neurochemical basis of pain from osteoblastic bone cancer (Aims 1 & 2), and we expect to prove for the first time that pain from osteoblastic and osteolytic bone cancers is caused both by tumors themselves, and by cancer-induced skeletal destruction (Aims 3 & 4). The results will be significant because they will provide rationale and direction for developing novel, mechanistically based treatments of bone cancer pain.